Key studies in nonmyeloid cell phagocytosis.
Abstract
As professional phagocytes, myeloid cells, including macrophages, dendritic cells, and neutrophils, are often the targets for investigation and analysis of phagocytosis. Phagocytosis, however, has also been observed in nonmyeloid cells, including epithelium, mesenchymal, and smooth muscle cells. Colloquially known as nonprofessional phagocytes, these nonmyeloid cells are capable of phagocytosis of pathogenic material and efferocytosis of apoptotic bodies. Cells, such as those found in the epithelium, are often the primary site for viral and bacterial infection and have evolved to possess strong anti-pathogenic machinery of their own. The processes by which nonmyeloid cells can engage in phagocytic functions have wide implications for tissue homeostasis and disease pathogenesis, including infection and colonization. This chapter will review the phagocytosis capabilities in these nonmyeloid cells.
Keywords
- efferocytosis
- epithelial cells
- internalization
- barrier
- nonprofessional
- opsonization
- trigger phagocytosis
- zipper phagocytosis
1. Introduction
As professional phagocytes, myeloid cells, including neutrophils, macrophages, monocytes, mast cells, and dendritic cells, are actively recruited to sites of tissue damage, infection, and inflammation playing a key role in host defense [1]. Of these, neutrophils and macrophages are perhaps the most widely studied in terms of their roles in phagocytosis [2, 3, 4]. However, there is increasing evidence that nonmyeloid cells, including epithelial [5, 6] endothelial [7, 8, 9], mesenchymal [7, 10, 11, 12], and smooth muscle cells [13, 14, 15, 16], can also engage in phagocytosis, or phagocytic-like mechanisms when phagocytosis is not their principal function. Phagocytosis by nonprofessional phagocytes is often referred to as internalization or even cannibalism, especially in the case of efferocytosis of apoptotic neighboring cells [17]. Nonprofessional phagocytes were first distinguished from professional phagocytes as early as 1970 after Rabinovitch demonstrated particulate uptake in fibroblasts [18, 19], although reports had demonstrated particulate uptake in nonmyeloid cells almost 40 years prior [20]. Since this initial observation, many nonprofessional phagocytes have been identified to have the phagocytic capacity and the capacity to clear potentially dangerous pathogens [21]. Table 1 includes a summary of these cell types and the roles that they have been observed to play in phagocytosis. Compared to professional phagocytes, nonmyeloid cells engage in distinctively different mechanisms to recognize, engulf, and destroy pathogens through phagocytosis. Nonprofessional phagocytes are demonstrably less efficient and lack factors such as Pattern Recognition Receptors (PRRs) capable of recognizing Pathogen Associated Molecular Patterns (PAMPs), as well as reactive oxygen species (ROS) and degradation enzymes required for effective clearance and degradation [19]. Nonmyeloid cells, however, provide a significant contribution toward the clearance of exogenous pathogens, cellular debris, and apoptotic bodies
Nonmyeloid cell | Cell subtype | Phagocytosis | Key findings | Ref’ |
---|---|---|---|---|
Epithelial | Hu. respiratory | Pathogen clearance | [22] | |
Hu. bladder, lung, ileocecal | Pathogen clearance | Involvement of an N-glycosylated protein receptor required for internalization. | [23] | |
Hu. T84 monkey kidney | Pathogen clearance | Ineffective phagolysosome maturation in epithelium. | [24] | |
MDCK, Hu. 16HBE14o- | Pathogen clearance | [25] | ||
Hu. A549 | Pathogen clearance | Containment of pathogen colonization by epithelium. | [26] | |
Hu. A549 | Pathogen clearance | Less efficient than professional phagocytes. | [27] | |
CHO cells | Pathogen clearance | Heparin/Heparan-dependent internalization of pathogen. | [28] | |
Ms. mammary | Efferocytosis | Receptor mediated engulfment | [29] | |
Hu. BEAS-2B Ms. HBEC Ms. MLE-12 | Efferocytosis | Uptake induces anti-inflammatory cytokine release | [30] | |
Hu. Thymus | Efferocytosis | Uptake relies on PSR and SR-B1. | [31] | |
Rt. bladder | Efferocytosis | Epithelial clearance of erythrocytes | [32] | |
Hu. hepatic biliary | Efferocytosis | PSR-mediated clearance results in chemokine increase. | [33] | |
Hu. A549 | Efferocytosis | Receptor-mediated recognition of apoptotic bodies. | [34] | |
Rt. Kidney | Efferocytosis | KIM-1 recognition internalizes apoptotic bodies. | [35] | |
CHO cells | Efferocytosis | LOX-1 recognition of apoptotic bodies. | [36] | |
Ms. retinal pigment | Efferocytosis | Role of ABCF1 recognition in apoptotic bodies. | [37] | |
Ms. HBEC | Efferocytosis | Efferocytosis by epithelium avoids IL-33-mediated inflammation. | [38] | |
Hu. ARPE-19 | Efferocytosis | Increased efficiency over macrophages in apoptotic clearance. | [39] | |
Ms. follicular | Efferocytosis | Clearance of apoptotic neighboring cells. | [40] | |
Ms. colonic | Efferocytosis | Role for BAI-1 mediated uptake in controlling inflammation. | [41] | |
Ms. retinal | Phagocytosis (Photo receptor material) | Gas6 & Protein S ligands for TAM-mediated phagocytosis. | [42] | |
Endothelial | Hu. vascular | Pathogen clearance | Rho kinase in endothelial cells bind listeria and internalization mediated by formins. | [43] |
Ms. Hepatic sinusoidal | Efferocytosis | IL-1 enhanced scavenging of apoptotic bodies. | [44] | |
Ms. Endothelium | Efferocytosis | SCARF1 mediated clearance of apoptotic bodies. | [45] | |
Bovine Aortic | Efferocytosis | LOX-1 recognition of apoptotic bodies. | [36] | |
Hu. umbilical vein | Phagocytosis platelet clearance | PS recognition on platelets-mediated phagocytosis. | [46] | |
Ms. (brain) microvascular | Phagocytosis myelin clearance | IgG opsonization is required for endothelial cell clearance, inducing endothelial-mesenchymal transition. | [47] | |
Mesenchymal | Hu. MRC5 cells | Pathogen clearance | Actin-dependent uptake. LAMP-1 mediated phagolysosome maturation. | [27] |
Hamster embryonic fibroblasts | Pathogen clearance Efferocytosis | ConA-dependent zipper phagocytosis. | [48] | |
Ms. ESCs | Efferocytosis | Inefficient (relative to macrophages) but effective clearance of apoptotic bodies. | [11] | |
Hu. BM-MSCs | Efferocytosis | Observation of mesenchymal stem cell efferocytosis enhancing inflammation. | [10] | |
Smooth muscle | Hu. vascular | Efferocytosis | PS-PSR mediated phagocytosis. | [16] |
Pigeon vascular | Phagocytosis (cholesterol) | First identification of smooth muscle cell-derived foam cells. | [49] | |
Ms. aortic | Phagocytosis (cholesterol) | Smooth muscle cells differentiate to a macrophage phenotype after cholesterol loading. | [50] | |
Hepatic | Hu. primary Stellate cells Hu. Hep G2 cells | Efferocytosis | Apoptotic clearance causes fibrogenic response. | [51] |
Rt. hepatocytes | Phagocytosis (lecithin-coated particles) | Exogenous substance uptake by hepatocytes. | [52] | |
Other | Rt. Sertoli cells | Efferocytosis | PS mediated clearance. | [53] |
Hu. Mesangial Kidney | Efferocytosis | CD36 independent clearance of apoptotic bodies. | [54] | |
Ms. neuronal progenitor | Efferocytosis | Identifies neuronal precursors as nonprofessional phagocyte. | [55] | |
Rt. chondrocytes | Phagocytosis (cartilage fragments) | CD163+ chondrocytes have phagocytic role in arthritis. | [56] |
2. Pathogen-induced phagocytosis
The active role of the host cell in the process of pathogen internalization, involving cytoskeletal rearrangements after pathogen recognition, ultimately distinguishes nonprofessional phagocytosis from infection [7, 19, 57]. There may be a few exceptions to this rule, such as Rotaviruses, known to gain infectious entry into the cell using the zipper mechanism, described below [58]. Internalization of the pathogen is, however, only the initial stage in the bigger mechanism of phagocytosis. The pathogen-containing internalized vesicle, otherwise known as the early phagosome, requires subsequent fusion with lysosomes in order to achieve pathogen killing [59]. The early phagosome matures by fusion with internal endocytic vesicles [59], recruiting factors, such as Rab5 [60], a small GTPase important for the maturation of the phagosome, and early endosome antigen 1 (EEA1) [61]. Rab5 remains transiently expressed in the early phagosome, directing the fusion of early endosomes [62, 63]. The schematic in Figure 1 depicts the process of endosome formation, maturation, and role of Rab proteins in phagocytosis. Rab5 has been extensively studied and understood in myeloid cells during professional phagocytosis and has also been shown to be constitutively expressed in nonmyeloid cells, including epithelial cells [64, 65, 66], fibroblasts [66], and smooth muscle cells [67], controlling the phagocytic processes. Rab5 is considered a master regulator of early endosome formation and trafficking to the early phagosome. Rab5 expressing early phagosomes initiates the process of pathogen killing or apoptotic recycling by creating a mildly acidic microenvironment (pH 6.1) within the phagosome and engaging in relatively low levels of hydrolysis [68]. Rab conversion is a term used to convey phagosome maturation beyond the early phagosome. Maturation involves the recruitment of Rab7, functionally replacing Rab5 in the phagosome [69]. Rab7, like Rab5, is a member of the GTPase family that manages the maturation of phagosomes and recruits other factors, such as the RAB7 interacting lysosomal protein (RILP), necessary for later phagosome fusion with lysosomes [70]. Formation of a late-stage phagosome also requires the recruitment of Lysosomal-Associated Membrane Process-1(LAMP-1), necessary for lysosomal fusion [27, 71] Rab7 functionally interacts with RILP [70, 72], resulting in lysosomal fusion with the late-stage phagosome. Consequently, the phagolysosome structure is formed, creating a more acidic environment (pH 5.5) and generating a cocktail of degradation enzymes and ROS in effort to kill invading pathogens or break down apoptotic bodies [57]. While the process leading to the formation of the phagolysosome is similar, the recognition of the pathogen by nonmyeloid cells and internalization can occur through one of several known pathways. These pathways, including efferocytosis, zipper phagocytosis, trigger phagocytosis, and opsonization, are discussed in more detail below.
2.1 Efferocytosis
Efferocytosis of apoptotic cells is the primary phagocytosis mechanism utilized by nonmyeloid cells. Recognition of apoptotic bodies is, therefore, critical for the clearance of apoptotic cells, and tissues have evolved ligand-receptor-based recognition as part of the initial engagement ultimately triggering efferocytosis of the apoptotic cell [7, 73, 74]. The primary component of this mechanism is the recognition of phosphatidylserine expressed in apoptotic cells [75]. During early apoptosis, phosphatidylserine molecules translocate to the cells’ surface, anchoring to the membrane, where they act as an “eat-me” signal to localized phagocytes, both professional and nonprofessional [76]. Phosphatidylserine can be recognized by several receptors, including integrins αvβ3 and αvβ5 [9, 29, 34]. CD36 [29, 34], CD91 [29], and even bio-specific phosphatidylserine receptors [16, 77]. Other ligands have been proposed to induce receptor-mediated efferocytosis of apoptotic cells by neighboring nonprofessional phagocytes, including Apoptosis Inhibitor of Macrophage (AIM) recognition by Kidney Injury Molecule-1 (KIM-1) [78] and milk fat globule-epidermal growth factor 8 (MFG-E8) by integrin αvβ3 [79].
2.2 “Zipper” phagocytosis
In the initial stages of nonmyeloid cell phagocytosis, one of the primary processes is the “Zipper” mechanism [6, 80, 81]. The zipper mechanism was first coined in 1975 by Griffin
2.3 “Trigger” phagocytosis
In contrast to zipper phagocytosis, the “trigger mechanism” is a process where engagement of the pathogen with a pathogen recognition receptor is not a critical component of the process. Some engagement with cell surface ligands may occur to secure the pathogen to the cell [80]; however, the distinguishable difference in trigger phagocytosis is that the pathogen “injects” effectors into the host cell. The injected components known as type-III (T3SS) [85] and type-IV (T4SS) [86] secretion systems result in host cell cytoskeletal rearrangements localized to the site of pathogen contact. Rearrangement generates “ruffles” along the cell surface, which then fold over the pathogen and fuse, internalizing the pathogen (Figure 2) [80].
2.4 Antibody opsonization
Emerging data suggest a potential role for opsonin-mediated phagocytosis in nonmyeloid cells [87, 88, 89, 90, 91, 92, 93]. Classical membrane-bound Fcγ receptors, namely FcγRI, FcγRII, and FcγRIII, and their capacity to recognize immunoglobulins are more typically associated with myeloid cell-based professional phagocytosis [57]. A more poorly understood, and somewhat atypical, class of immunoglobulin receptor, known as the neonatal Fc receptor (FcRn), is expressed ubiquitously throughout multiple tissue types, including pulmonary epithelium [92], intestinal epithelium [87], microvascular endothelium [91], and the placenta [89]. It was initially thought that FcRn is expressed in fetal and neonatal tissues; however, it has since been demonstrated that expression is sustained throughout life [90]. The FcRn has a strong affinity for albumin [90] and IgG antibodies [88]. IgG-mediated phagocytosis
3. Epithelial cell phagocytosis
The primary function of epithelial cells is to form a barrier between the internal organs and the external environment. As such these tissues have evolved to be relatively efficient in anti-pathogenic mechanisms, including the secretion of antimicrobial peptides, functional mucociliary clearance, and phagocytosis [6, 7]. The integumentary skin layer is perhaps the most obvious epithelial cell layer; however, the epithelium also lines internal organs and mucosal surface tissues, such as the respiratory tract, digestive system, genitourinary organs, and neuronal tissues, among others [95]. The physiological organization and structure of the epithelium can vary, even within the same organ system, for example, the pseudostratified epithelium that lines the proximal airways progressively changes to a simple squamous epithelium that lines the alveolar airspace [96, 97]. Despite the multiple structural phenotypes, the primary function of any epithelium is to form a barrier, a protective layer of epithelial cells connected by tight junctions [98]. Tissue-resident myeloid cells, such as macrophages, are often labeled as the first line of defense when it comes to invading pathogens; however, it could be argued that epithelial cells provide that initial functional defense [6].
Efferocytosis appears to be a function of practically all tissues and cell types [7, 73]. Relative to professional phagocytes. The removal of damaged or dying cells can leave the barrier exposed and prone to further damage or infection. As such epithelial tissues have a remarkable capacity for repair to maintain barrier integrity and homeostasis [98]. It is well established that the primary mechanism to eliminate apoptotic epithelial cells is through extrusion into the external apical lumen [6, 99]; however, epithelial cells also engage in efferocytosis [7]. Efferocytosis is particularly important for subapical apoptotic bodies or if the epithelial lumen does not have a functional system for debris removal such as mucociliary clearance in the airways.
Apoptotic epithelia can express a wide array of “eat me” signals with the most common being phosphatidylserine [21, 29, 34]. Recognition of apoptotic cells by epithelia is somewhat less understood; however, uptake of apoptotic bodies and recognition by phosphatidylserine receptors on the epithelial cells are acknowledged to be an integral part of this process [34]. Some studies provide evidence that the process of efferocytosis observed in epithelia is distinct from that of professional phagocytes and even from other phagocytic processes [74]. Epithelial cells have a relatively strong expression of PRRs with innate capabilities of recognizing exogenous PAMPs [5, 6, 100, 101]. Activation of PRRs can induce strong inflammatory responses including cytokine release [102], however mucosal epithelial cells must maintain a bio-symbiotic relationship with natural bacterial flora and control the potential for excessive inflammatory stimulation [103]. To achieve this, many of the PRRs are either intracellular [103, 104, 105, 106] to recognize pathogens in the process of infecting the epithelium or on the surface of a polarized epithelium restricted to the basolateral surface [101, 107] to detect pathogens that have breached the epithelial barrier. PRRs expressed on epithelial cells include the Toll-Like Receptors (TLRs), the C-type Lectin Receptors (CLRs), the NOD-like Receptors (NLRs), and the RIG-I-like receptors (RLRs) [6, 108, 109]. It has also been proposed that PRRs can also engage in zipper phagocytosis, as integral parts of internalizing pathogenic stimuli, in addition to internalization of the receptor itself to control excessive inflammatory responses [110, 111, 112]; however, it is unclear if this pathogen-induced internalization is consistent with zipper phagocytosis or even conserved in nonmyeloid cells, in principle it is a possibility. Often the overarching inflammatory response is studied in isolation from that of any possible phagocytosis response. However, it is important to recognize that there is significant overlap and control of one by the other. Indeed, it has been reported that signaling factors, such as Rac1, are necessary for phagocytosis and the subsequent control of anti-inflammatory cytokine release, key to inflammatory resolution [30]. Further insights into epithelial cell phagocytosis may well be found in the study of inflammatory cytokine biology.
A common place for epithelial phagocytosis study can be found in the retinal epithelium of the eye [113]. Separated by the blood-retina barrier [114, 115], the retinal epithelium is able to maintain a certain level of immune privilege from circulating leukocytes [116]. Whilst there is evidence for resident and infiltrating myeloid cells in these tissues [117], it is primarily the retinal epithelium that maintains homeostasis through phagocytic functions [113]. Aside from immune recognition, phagocytosis by the retinal epithelium is important for the biological process of photoreception [118]. The distal portions of photoreceptors in the eye, known as “Photoreceptor Outer Segments” (POS) are in direct contact with the retinal epithelium [119] and rich in membranous discs packaged with proteins known as opsins [120], which are photosensitive. Exposure to light bleaches opsins to allow for signal transduction [121]. Extended exposure to these opsin-rich discs results in phototoxic damage and mature discs are shed from the distal tip to allow for the synthesis of new discs [113]. The retinal epithelium is perpetually “ensheathed” around the distal tips of photoreceptors [122], which upon shedding are phagocytosed into the retinal epithelium [119, 123]. The phagosome undergoes phagolysosomal maturation, including acidification and breakdown of the photoreceptor distal tips [113]. This entire process allows for the maintenance of long-term photoreceptors with short-lived distal tips by the retinal epithelial cells in an immune-privileged tissue. The retinal epithelium represents a prime example of a nonmyeloid cell performing specialized phagocytosis as a primary function in the homeostatic maintenance of its niche.
Internalization of pathogens by mucosal epithelium is well documented [5, 22, 23, 24, 25, 26, 27]. Epithelial cells utilize both zipper and trigger mechanisms to internalize invading pathogens and engage in phagocytosis [6]. After internalization of the pathogen, the maturation of the phagosome in epithelia is akin to that of professional phagocytes [59], including markers of maturation, phagosome acidification, and lysosomal fusion [124]. The primary difference lies in the speed and efficiency when compared to professional phagocytes [125]. Despite this lack of efficiency, the contribution of phagocytosis of epithelial cells is still remarkably significant when considering cell numbers and so the impact of epithelial cell phagocytosis in pathogen clearance should not be ignored, having distinctive implications in both homeostasis and disease.
4. Endothelial cell phagocytosis
Like epithelial cells, endothelial cells also form a physical barrier, specifically in the walls of fluid systems, such as the circulatory and lymphatic systems [126]. These barriers comprise squamous endothelial cells, which form a single cell layer lining the entire system [126]. Their primary functions are to maintain the barrier and act as a filtration system for fluid-containing cells or substances into, and out of, the circulatory system [127, 128]. Significant cross talk occurs between endothelial cells and professional phagocytes as the endothelium allows leukocytes to cross through the barrier into tissues during times of infection and stress [129]. The concept of endothelial cells acting as phagocytes is not new, with some reports dating back as early as the 1920s [130]. Such a process is important for the endothelium to maintain circulatory homeostasis with effective phagocytic clearance mechanisms [129]. Phagocytosis is clearly an important function for endothelial cells to possess and execute efficiently, failure to do so can lead to serious complications such as stroke [131, 132]. Due to its importance, phagocytic clearance by endothelial cells has been termed “Angiophagy” [131, 132].
In situations of physical damage to endothelial tissue, endothelial cells can often be the first to encounter potentially pathogenic insults, particularly pathogens that enter circulation. Like epithelial cells, endothelial cells strongly express PRRs, including TLRs, NLRs, and RIG receptors [133, 134, 135, 136, 137]. During times of inflammation, endothelial cell PRR expression is increased [138], an important process for innate recognition of potentially invasive pathogens. It is also imperative for endothelial cells to recognize endogenous material, such as aged red blood cells, to both prevent and clear micro emboli blockages [139]. Endothelial cells express Lectin-like oxLDL receptor 1 (LOX-1), a transmembrane protein that is capable of recognizing these aged red blood cells that express phosphatidylserine [36]. Endothelial cells can also clear other cellular material, such as apoptotic cell bodies of circulating leukocytes, including that of circulating professional phagocytes, such as neutrophils [140], and do so
Angiophagy, as a phagocytic process, can be considered distinct from other mechanisms such as efferocytosis, as a specialized method of clearing vascular occlusions, which may or may not have “eat-me” recognition molecules. In several organ systems, angiophagy of large particulates, such as blood clots and fibrin, has been observed by endothelial cells in microvascular capillary structures, releasing the phagocytosed particles into the basolateral parenchyma [132, 142]. While the overall result remains consistent, angiophagy efficiency can vary between different organs [142]. The biomechanical processes of angiophagy are not well understood. Studies have demonstrated that projections of the endothelial cell wall known as “lamellipodia” extend into the occluded lumen after extensive cellular remodeling [142]. Engulfment of the occluding body occurs within a few hours, relatively quickly when compared to the entire angiophagy process, which can take several days. Post engulfment, the occluding body is trafficked to the underlying tissue where it can be further processed, often by myeloid cells [142]. A more comprehensive characterization, beyond engulfment in angiophagy, is lacking although mechanisms of phagocytosis are certainly present. Further reports have demonstrated that microparticles are internalized and retained intracellularly without any impact on barrier integrity [143].
A common endpoint of phagocytosis in some professional phagocytes is antigen presentation. After a functional inactivation of the pathogen, components of the pathogen are “presented” on the cellular surface of the phagocyte and used to activate specific lymphocytes, to initiate adaptive immune responses. This specialized function of antigen presentation is typically associated with dendritic cells but is also observed in other myeloid cells. Interestingly, antigen presentation has been observed in endothelial cells [144, 145], and even express MHCII, typically restricted to professional antigen-presenting cells, as a result of inflammatory stimulation [146]. As endothelial cells are not professional antigen-presenting cells and lack migrating capabilities important for effective antigen presentation, it is somewhat unclear as to why endothelial cells have developed antigen-presentation capabilities. It has been postulated to be important for T-cell-specific trafficking to sites of infection and stress [144]. Either way, strong phagocytosis machinery is required to process and present antigens on the cell surface.
Phagocytosis for endothelial cells is an important homeostatic process that allows luminal vasculature to remain clear of blockages and underlying tissues to remain clear of potentially pathogenic infection. The process of angiophagy to allow the extravasation of occlusions, and restoring luminal perfusion is arguably unique to endothelial cells as a process that even myeloid cells do not possess. Further work on the capabilities of endothelial cell phagocytosis could well lead to a better understanding and even treatment options for serious acute macro and microvascular disease.
5. Mesenchymal stem cell phagocytosis
Mesenchymal stem cells (MSCs) are multipotent cells capable of regeneration and differentiation into multiple cell types [147]. They reside in a wide number of tissues and give rise to cells and tissues necessary for growth, development, and tissue repair. MSCs are frequently referred to as adult stem cells, along with hematopoietic stem cells (HSCs), which of course give rise to professional phagocytes. Adult stem cells, such as MSCs, are multipotent and distinguished from embryonic stem cells (ESCs) or laboratory-generated induced pluripotent stem cells (iPSCs), which are pluripotent with a differentiation capacity to generate cells of all three germ layers. MSCs are stromal cells, and distinct from their HSC counterparts, it is therefore perhaps surprising that an advanced cellular function such as phagocytosis has been observed. Several reports, however, have demonstrated that MSCs are indeed capable of phagocytosis. This was first reported in 2000 by Wood
MSCs do possess a certain level of PRRs, including TLRs [152] and NOD-like receptors [153]; however, reports are lacking that definitively demonstrate exogenous pathogen phagocytosis although have suggested its plausibility [154]. Similar to endothelial cells, MSCs are capable of MHC-II type antigen presentation [155], considered to be unique to professional phagocytes, and these antigen-presenting MSCs are capable of presenting and activating T cells [156, 157]. This would suggest that phagocytosis of pathogens, to present antigens
6. Smooth muscle cell phagocytosis
Smooth muscle is found in multiple organ systems and can provide a variety of roles, often important for the physical functions of the organ or tissue in which they reside. Unlike skeletal muscle, smooth muscle involuntarily can maintain its tone over extended periods of time [158]. The functional cellular units of smooth muscle are described as nonstriated, in that they lack the sarcomeres that their skeletal striated counterparts possess. Smooth muscle cells are rich in actin and myosin which allows for efficient contraction [159]. It would be easy to describe smooth muscle cells (SMCs) as monofunctional and homogenous; however, it would appear that they have stromal-like properties and are capable of further differentiation into multiple “macrophage-like” phenotypes capable of phagocytosis [160]. The concept of phagocytosis by SMCs was first suggested observed in 1971 by Campbell and colleagues [161], and later confirmed by Garfield
Atherosclerosis is the buildup of plaques in the subendothelial tissues of arterial macrovascular walls [164]. These plaques can obstruct blood flow through the arterial lumen, which can result in a series of vascular-related diseases. Atherosclerotic plaques comprise of “foam cells,” which have phagocytosed low-density lipoproteins, which they are seemingly unable to efficiently process and resolve. Foam cells as active phagocytes are myeloid in origin, more specifically they are macrophages derived from monocytes [165] recruited into the subendothelial tissues as a result of vascular damage. However, foam cells of atherosclerotic plaques can also be derived from SMCs [49, 166], with some reports even suggesting the majority of foam cells in atherosclerotic legions to be of SMC origin [167]. Such SMCs resemble an undifferentiated precursor capable of a phenotypic switch under varying conditions [168]. The specific conditions that trigger SMCs to switch to a macrophage-like foam cell are not well known, although it appears to be KLF-4 dependent [169]. SMCs have a high abundance of LRP1, a key scavenger receptor for lipoproteins [170]. LRP1 activation will result in an influx of lipoproteins into the cell, generating a “foam cell” phenotype [171]. It is the inefficiency of SMC-derived foam cells as phagocytes that appears to be a significant factor in atherosclerosis. Despite the recognition that phagocytosis, or lack thereof, by SMCs is clearly playing a significant role in the pathophysiology of atherosclerosis, little is known about the internalization mechanism compared to the process of autophagy [172]. Studies to date have mainly focused their efforts to recreate SMC-derived foam cells and compare them to foam cells of macrophage origin in attempts to highlight key differences, instead of addressing the specific mechanisms relating to phagocytosis in SMC-derived foam cells.
7. Conclusions
Historically most investigations with regard to phagocytosis have focused on the role of myeloid cells as professional phagocytes. In this review, we have discussed nonmyeloid cell types, where roles in phagocytosis have been established. It is becoming increasingly evident that many tissue types are capable, to some extent, of phagocytosis [173]. Indeed, there are even situations of specialized phagocytic function, such as that observed in the retinal epithelia and angiophagy in vascular endothelial cells. Despite nonprofessional phagocytes being less effective when it comes to pathogen recognition, internalization, phagosome maturation, and pathogen killing, they still provide a significant contribution to phagocytosis, and, in more immune-privileged tissues, phagocytosis by nonprofessional phagocytes is imperative to maintain physiological functions.
Acknowledgments
ALR is supported by Cystic Fibrosis Foundation awards FIRTH21XX0 and FIRTH17XX0 and the Tyler Health and Education Fund.
References
- 1.
Stegelmeier AA et al. Myeloid cells during viral infections and inflammation. Viruses. 2019; 11 (2):168-193 - 2.
Silva MT, Correia-Neves M. Neutrophils and macrophages: The main partners of phagocyte cell systems. Frontiers in Immunology. 2012; 3 :174 - 3.
Kantari C, Pederzoli-Ribeil M, Witko-Sarsat V. The role of neutrophils and monocytes in innate immunity. Contributions to Microbiology. 2008; 15 :118-146 - 4.
Dale DC, Boxer L, Liles WC. The phagocytes: Neutrophils and monocytes. Blood. 2008; 112 (4):935-945 - 5.
Sharma L et al. Mechanisms of epithelial immunity evasion by respiratory bacterial pathogens. Frontiers in Immunology. 2020; 11 :91 - 6.
Günther J, Seyfert HM. The first line of defence: Insights into mechanisms and relevance of phagocytosis in epithelial cells. Seminars in Immunopathology. 2018; 40 (6):555-565 - 7.
Sihombing M et al. Unexpected role of nonimmune Cells: Amateur phagocytes. DNA and Cell Biology. 2021; 40 (2):157-171 - 8.
Visan I. Amateur phagocytes. Nature Immunology. 2019; 20 (3):245-245 - 9.
Kirsch T et al. Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses. Blood. 2007; 109 (7):2854-2862 - 10.
Tso GH et al. Phagocytosis of apoptotic cells modulates mesenchymal stem cells osteogenic differentiation to enhance IL-17 and RANKL expression on CD4+ T cells. Stem Cells. 2010; 28 (5):939-954 - 11.
Wood W et al. Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development. 2000; 127 (24):5245-5252 - 12.
Zhang Z et al. Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2. eBioMedicine. 2019; 45 :341-350 - 13.
Bennett MR et al. Binding and phagocytosis of apoptotic vascular smooth muscle cells is mediated in part by exposure of phosphatidylserine. Circulation Research. 1995; 77 (6):1136-1142 - 14.
Garfield RE, Chacko S, Blose S. Phagocytosis by muscle cells. Laboratory Investigation. 1975; 33 (4):418-427 - 15.
Gordon-Weeks P, Gabella G. Degeneration of varicose axons and their phagocytosis by smooth muscle cells. Journal of Neurocytology. 1977; 6 (6):711-721 - 16.
Kolb S et al. The phosphatidylserine receptor mediates phagocytosis by vascular smooth muscle cells. The Journal of Pathology. 2007; 212 (3):249-259 - 17.
Fais S. Cannibalism: A way to feed on metastatic tumors. Cancer Letters. 2007; 258 (2):155-164 - 18.
Rabinovitch M. Mononuclear Phagocytes. Oxford: Blackwell Scientific Publishers; 1970. pp. 299-315 - 19.
Rabinovitch M. Professional and non-professional phagocytes: An introduction. Trends in Cell Biology. 1995; 5 (3):85-87 - 20.
Mudd S, McCutcheon M, Lucké B. Phagocytosis. Physiological Reviews. 1934; 14 (2):210-275 - 21.
Schwegler M et al. Clearance of primary necrotic cells by non-professional phagocytes. Biology of the Cell. 2015; 107 (10):372-387 - 22.
Plotkowski MC et al. Pseudomonas aeruginosa internalization by human epithelial respiratory cells depends on cell differentiation, polarity, and junctional complex integrity. American Journal of Respiratory Cell and Molecular Biology. 1999; 20 (5):880-890 - 23.
Fumagalli O et al. N-glycosylated proteins are involved in efficient internalization of Klebsiella pneumoniae by cultured human epithelial cells. Infection and Immunity. 1997; 65 (11):4445-4451 - 24.
Watson RO, Galán JE. Campylobacter jejuni survives within epithelial cells by avoiding delivery to lysosomes. PLoS Pathogens. 2008; 4 (1):e14 - 25.
Capasso D et al. Elimination of Pseudomonas aeruginosa through Efferocytosis upon binding to apoptotic Cells. PLoS Pathogens. 2016; 12 (12):e1006068 - 26.
Cortés G et al. Role of lung epithelial cells in defense against Klebsiella pneumoniae pneumonia. Infection and Immunity. 2002; 70 (3):1075-1080 - 27.
Couzinet S et al. Phagocytic uptake of Encephalitozoon cuniculi by nonprofessional phagocytes. Infection and Immunity. 2000; 68 (12):6939-6945 - 28.
Herrera EM et al. Mediation of Trypanosoma cruzi invasion by heparan sulfate receptors on host cells and penetrin counter-receptors on the trypanosomes. Molecular and Biochemical Parasitology. 1994; 65 (1):73-83 - 29.
Monks J et al. Epithelial cells as phagocytes: Apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death and Differentiation. 2005; 12 (2):107-114 - 30.
Juncadella IJ et al. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature. 2013; 493 (7433):547-551 - 31.
Cao WM et al. Phosphatidylserine receptor cooperates with high-density lipoprotein receptor in recognition of apoptotic cells by thymic nurse cells. Journal of Molecular Endocrinology. 2004; 32 (2):497-505 - 32.
Wakefield JS, Hicks RM. Erythrophagocytosis by the epithelial cells of the bladder. Journal of Cell Science. 1974; 15 (3):555-573 - 33.
Rong G-H et al. Human intrahepatic biliary epithelial cells engulf blebs from their apoptotic peers. Clinical and Experimental Immunology. 2013; 172 (1):95-103 - 34.
Sexton DW, Blaylock MG, Walsh GM. Human alveolar epithelial cells engulf apoptotic eosinophils by means of integrin- and phosphatidylserine receptor-dependent mechanisms: A process upregulated by dexamethasone. The Journal of Allergy and Clinical Immunology. 2001; 108 (6):962-969 - 35.
Ichimura T et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. The Journal of Clinical Investigation. 2008; 118 (5):1657-1668 - 36.
Oka K et al. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95 (16):9535-9540 - 37.
Guo F et al. ABCF1 extrinsically regulates retinal pigment epithelial cell phagocytosis. Molecular Biology of the Cell. 2015; 26 (12):2311-2320 - 38.
Penberthy KK, Juncadella IJ, Ravichandran KS. Apoptosis and engulfment by bronchial epithelial cells. Implications for allergic airway inflammation. Annals of American Thoracic Society. 2014; 5 (Suppl. 5):S259-S262 - 39.
Petrovski G et al. Clearance of dying ARPE-19 cells by professional and nonprofessional phagocytes in vitro- implications for age-related macular degeneration (AMD). Acta Ophthalmologica. 2011; 89 (1):e30-e34 - 40.
Mesa KR et al. Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool. Nature. 2015; 522 (7554):94-97 - 41.
Lee CS et al. Boosting apoptotic cell clearance by colonic epithelial Cells attenuates inflammation In vivo. Immunity. 2016; 44 (4):807-820 - 42.
Burstyn-Cohen T et al. Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron. 2012; 76 (6):1123-1132 - 43.
Rengarajan M, Hayer A, Theriot JA. Endothelial cells use a formin-dependent phagocytosis-like process to internalize the bacterium listeria monocytogenes. PLoS Pathogens. 2016; 12 (5):e1005603 - 44.
Dini L et al. Phagocytosis of apoptotic bodies by liver endothelial cells. Journal of Cell Science. 1995; 108 (Pt 3):967-973 - 45.
Ramirez-Ortiz ZG et al. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nature Immunology. 2013; 14 (9):917-926 - 46.
Ji S et al. Phagocytosis by endothelial cells inhibits procoagulant activity of platelets of essential thrombocythemia in vitro. Journal of Thrombosis and Haemostasis. 2020; 18 (1):222-233 - 47.
Zhou T et al. Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury. Nature Neuroscience. 2019; 22 (3):421-435 - 48.
Goldman R. Lectin-mediated attachment and ingestion of yeast cells and erythrocytes by hamster fibroblasts. Experimental Cell Research. 1977; 104 (2):325-334 - 49.
Cooke PH, Smith SC. Smooth muscle cells: The source of foam cells in atherosclerotic white Carneau pigeons. Experimental and Molecular Pathology. 1968; 8 (2):171-189 - 50.
Rong JX et al. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100 (23):13531-13536 - 51.
Canbay A et al. Apoptotic body engulfment by a human stellate cell line is Profibrogenic. Laboratory Investigation. 2003; 83 (5):655-663 - 52.
Soji T et al. Evidence that hepatocytes can phagocytize exogenous substances. The Anatomical Record. 1992; 233 (4):543-546 - 53.
Shiratsuchi A et al. Role of class B scavenger receptor type I in phagocytosis of apoptotic rat spermatogenic cells by Sertoli cells. The Journal of Biological Chemistry. 1999; 274 (9):5901-5908 - 54.
Hughes J et al. Human glomerular mesangial cell phagocytosis of apoptotic neutrophils: Mediation by a novel CD36-independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion. The Journal of Immunology. 1997; 158 (9):4389-4397 - 55.
Lu Z et al. Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nature Cell Biology. 2011; 13 (9):1076-1083 - 56.
Jiao K et al. The identification of CD163 expressing phagocytic chondrocytes in joint cartilage and its novel scavenger role in cartilage degradation. PLoS One. 2013; 8 (1):e53312 - 57.
Uribe-Querol E, Rosales C. Phagocytosis: Our current understanding of a universal biological process. Frontiers in Immunology. 2020; 11 :1066 - 58.
Arias CF, Silva-Ayala D, López S. Rotavirus entry: A deep journey into the cell with several exits. Journal of Virology. 2015; 89 (2):890-893 - 59.
Pauwels AM et al. Patterns, receptors, and signals: Regulation of phagosome maturation. Trends in Immunology. 2017; 38 (6):407-422 - 60.
Vieira OV et al. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. The Journal of Cell Biology. 2001; 155 (1):19-25 - 61.
Wilson JM et al. EEA1, a tethering protein of the early sorting endosome, shows a polarized distribution in hippocampal neurons, epithelial cells, and fibroblasts. Molecular Biology of the Cell. 2000; 11 (8):2657-2671 - 62.
Bucci C et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992; 70 (5):715-728 - 63.
Gorvel JP et al. rab5 controls early endosome fusion in vitro. Cell. 1991; 64 (5):915-925 - 64.
Balaji K et al. The RAB5-GEF function of RIN1 regulates multiple steps during Listeria monocytogenes infection. Traffic. 2014; 15 (11):1206-1218 - 65.
Saitoh S et al. Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells. Proceedings of the National Academy of Sciences of the United States of America. 2017; 114 (12):E2327-e2336 - 66.
Schnatwinkel C et al. The Rab5 effector Rabankyrin-5 regulates and coordinates different endocytic mechanisms. PLoS Biology. 2004; 2 (9):E261 - 67.
Tan JY et al. Rab5a-mediated autophagy regulates the phenotype and behavior of vascular smooth muscle cells. Molecular Medicine Reports. 2016; 14 (5):4445-4453 - 68.
Maxfield FR, McGraw TE. Endocytic recycling. Nature Reviews. Molecular Cell Biology. 2004; 5 (2):121-132 - 69.
Vieira OV et al. Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidylinositol 3-kinase. Molecular and Cellular Biology. 2003; 23 (7):2501-2514 - 70.
Cantalupo G et al. Rab-interacting lysosomal protein (RILP): The Rab7 effector required for transport to lysosomes. The EMBO Journal. 2001; 20 (4):683-693 - 71.
Huynh KK et al. LAMP proteins are required for fusion of lysosomes with phagosomes. The EMBO Journal. 2007; 26 (2):313-324 - 72.
Jordens I et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Current Biology. 2001; 11 (21):1680-1685 - 73.
Serizier SB, McCall K. Scrambled eggs: Apoptotic cell clearance by non-professional phagocytes in the Drosophila ovary. Frontiers in Immunology. 2017; 2017 :8 - 74.
Henson PM. Cell Removal: Efferocytosis. Annual Review of Cell and Developmental Biology. 2017; 33 :127-144 - 75.
Naeini MB et al. The role of phosphatidylserine recognition receptors in multiple biological functions. Cellular & Molecular Biology Letters. 2020; 25 (1):23 - 76.
Nagata S et al. Exposure of phosphatidylserine on the cell surface. Cell Death & Differentiation. 2016; 23 (6):952-961 - 77.
Jansen F et al. Endothelial microparticle uptake in target cells is annexin I/phosphatidylserine receptor dependent and prevents apoptosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012; 32 (8):1925-1935 - 78.
Arai S et al. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice. Nature Medicine. 2016; 22 (2):183-193 - 79.
Nakaya M et al. Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. The Journal of Clinical Investigation. 2017; 127 (1):383-401 - 80.
Swanson JA, Baer SC. Phagocytosis by zippers and triggers. Trends in Cell Biology. 1995; 5 (3):89-93 - 81.
Tollis S et al. The zipper mechanism in phagocytosis: Energetic requirements and variability in phagocytic cup shape. BMC Systems Biology. 2010; 4 :149 - 82.
Bianco C, Griffin FM Jr, Silverstein SC. Studies of the macrophage complement receptor. Alteration of receptor function upon macrophage activation. The Journal of Experimental Medicine. 1975; 141 (6):1278-1290 - 83.
Griffin FM Jr, Griffin JA, Silverstein SC. Studies on the mechanism of phagocytosis. II. The interaction of macrophages with anti-immunoglobulin IgG-coated bone marrow-derived lymphocytes. The Journal of Experimental Medicine. 1976; 144 (3):788-809 - 84.
Cieza RJ et al. The IbeA invasin of adherent-invasive Escherichia coli mediates interaction with intestinal epithelia and macrophages. Infection and Immunity. 2015; 83 (5):1904-1918 - 85.
Coburn B, Sekirov I, Finlay BB. Type III secretion systems and disease. Clinical Microbiology Reviews. 2007; 20 (4):535-549 - 86.
Wallden K, Rivera-Calzada A, Waksman G. Type IV secretion systems: Versatility and diversity in function. Cellular Microbiology. 2010; 12 (9):1203-1212 - 87.
Dickinson BL et al. Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. The Journal of Clinical Investigation. 1999; 104 (7):903-911 - 88.
Koenderman L. Inside-Out Control of Fc-Receptors. Frontiers in Immunology. 2019; 10 :544 - 89.
Leach JL et al. Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: Implications for maternal-fetal antibody transport. Journal of Immunology. 1996; 157 (8):3317-3322 - 90.
Roopenian DC, Akilesh S. FcRn: The neonatal fc receptor comes of age. Nature Reviews. Immunology. 2007; 7 (9):715-725 - 91.
Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal fc receptor (FcRn) at the blood-brain barrier. Journal of Neurochemistry. 2002; 81 (1):203-206 - 92.
Spiekermann GM et al. Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: Functional expression of FcRn in the mammalian lung. The Journal of Experimental Medicine. 2002; 196 (3):303-310 - 93.
Vidarsson G et al. FcRn: An IgG receptor on phagocytes with a novel role in phagocytosis. Blood. 2006; 108 (10):3573-3579 - 94.
Pyzik M et al. The neonatal fc receptor (FcRn): A misnomer? Frontiers in Immunology. 2019; 10 :1540 - 95.
Larsen SB, Cowley CJ, Fuchs E. Epithelial cells: Liaisons of immunity. Current Opinion in Immunology. 2020; 62 :45-53 - 96.
Groeger S, Meyle J. Oral mucosal epithelial cells. Frontiers in Immunology. 2019; 10 :208 - 97.
Proud D, Leigh R. Epithelial cells and airway diseases. Immunological Reviews. 2011; 242 (1):186-204 - 98.
Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Springer Harbor Perspective Biology. 2018; 10 (1):a029314 - 99.
Nanavati BN, Yap AS, Teo JL. Symmetry breaking and epithelial cell extrusion. Cells. 2020; 9 (6):cells9061416 - 100.
Pardo-Camacho C et al. Epithelial immunity: Priming defensive responses in the intestinal mucosa. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2018; 314 (2):G247-g255 - 101.
Weitnauer M, Mijošek V, Dalpke AH. Control of local immunity by airway epithelial cells. Mucosal Immunology. 2016; 9 (2):287-298 - 102.
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140 (6):805-820 - 103.
Wells JM et al. Epithelial crosstalk at the microbiota-mucosal interface. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108 :4607-4614 - 104.
Hennessy C, D.P. McKernan anti-viral pattern recognition receptors as therapeutic targets. Cells. 2021; 10 :cells10092258 - 105.
Hornef MW et al. Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. The Journal of Experimental Medicine. 2003; 198 (8):1225-1235 - 106.
Hill AA, Diehl GE. Identifying the patterns of pattern recognition receptors. Immunity. 2018; 49 (3):389-391 - 107.
Yu S, Gao N. Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance. Cellular and Molecular Life Sciences. 2015; 72 (17):3343-3353 - 108.
McClure R, Massari P. TLR-dependent human mucosal epithelial cell responses to microbial pathogens. Frontiers in Immunology. 2014; 5 :386 - 109.
Lavelle EC et al. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunology. 2010; 3 (1):17-28 - 110.
Moretti J, Blander JM. Insights into phagocytosis-coupled activation of pattern recognition receptors and inflammasomes. Current Opinion in Immunology. 2014; 26 :100-110 - 111.
Kingeter LM, Lin X. C-type lectin receptor-induced NF-κB activation in innate immune and inflammatory responses. Cellular & Molecular Immunology. 2012; 9 (2):105-112 - 112.
Goodridge HS, Simmons RM, Underhill DM. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. Journal of Immunology. 2007; 178 (5):3107-3115 - 113.
Kwon W, Freeman SA. Phagocytosis by the retinal pigment epithelium: Recognition, resolution, recycling. Frontiers in Immunology. 2020; 11 :604205 - 114.
Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. European Journal of Ophthalmology. 2011; 21 (Suppl. 6):S3-S9 - 115.
Lehmann GL et al. Plasma membrane protein polarity and trafficking in RPE cells: Past, present and future. Experimental Eye Research. 2014; 126 :5-15 - 116.
Taylor AW, Hsu S, Ng TF. The role of retinal pigment epithelial Cells in regulation of macrophages/microglial Cells in retinal Immunobiology. Frontiers in Immunology. 2021; 12 :91-100 - 117.
Ronning KE, Karlen SJ, Burns ME. Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration. Journal of Neuroinflammation. 2022; 19 (1):299 - 118.
Lakkaraju A et al. The cell biology of the retinal pigment epithelium. Progress in Retinal and Eye Research. 2020:100846 - 119.
Young RW, Bok D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. The Journal of Cell Biology. 1969; 42 (2):392-403 - 120.
Terakita A. The opsins. Genome Biology. 2005; 6 (3):213 - 121.
Masland RH. The neuronal Organization of the retina. Neuron. 2012; 76 (2):266-280 - 122.
Matsumoto B, Defoe DM, Besharse JC. Membrane turnover in rod photoreceptors: Ensheathment and phagocytosis of outer segment distal tips by pseudopodia of the retinal pigment epithelium. Proceedings of the Royal Society of London - Series B: Biological Sciences. 1987; 230 (1260):339-354 - 123.
LaVail MM. Rod outer segment disk shedding in rat retina: Relationship to cyclic lighting. Science. 1976; 194 (4269):1071-1074 - 124.
Blanchette CD et al. Decoupling internalization, acidification and phagosomal-endosomal/lysosomal fusion during phagocytosis of InlA coated beads in epithelial cells. PLoS One. 2009; 4 (6):e6056 - 125.
Saftig P. Physiology of the lysosome. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Chapter 3. Oxford: Oxford PharmaGenesis; 2006 - 126.
Potente M, Mäkinen T. Vascular heterogeneity and specialization in development and disease. Nature Reviews. Molecular Cell Biology. 2017; 18 (8):477-494 - 127.
Satchell SC, Braet F. Glomerular endothelial cell fenestrations: An integral component of the glomerular filtration barrier. American Journal of Physiology. Renal Physiology. 2009; 296 (5):F947-F956 - 128.
Luissint A-C et al. Tight junctions at the blood brain barrier: Physiological architecture and disease-associated dysregulation. Fluids and Barriers of the CNS. 2012; 9 (1):23 - 129.
Stolarz AJ et al. Opinion: Endothelial Cells - macrophage-like gatekeepers? Frontiers in Immunology. 2022; 13 :902945 - 130.
Doan CA, Sabin FR. Normal and pathological fragmentation of red blood cells; the phagocytosis of these fragments by desquamated endothelial cells of the blood stream; the correlation of the peroxidase reaction with phagocytosis in mononuclear cells. The Journal of Experimental Medicine. 1926; 43 (6):839-850 - 131.
Grutzendler J. Angiophagy: Mechanism of microvascular recanalization independent of the fibrinolytic system. Stroke. 2013; 44 (6 Suppl. 1):S84-S86 - 132.
Lam CK et al. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature. 2010; 465 (7297):478-482 - 133.
Opitz B et al. Role of toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections. Thrombosis and Haemostasis. 2009; 102 (6):1103-1109 - 134.
Mitchell JA et al. Role of pattern-recognition receptors in cardiovascular health and disease. Biochemical Society Transactions. 2007; 35 (Pt 6):1449-1452 - 135.
Salvador B et al. Modulation of endothelial function by toll like receptors. Pharmacological Research. 2016; 108 :46-56 - 136.
Nagyőszi P et al. Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells. Journal of Neurochemistry. 2015; 135 (3):551-564 - 137.
Xu S, Jin T, Weng J. Endothelial Cells as a key cell type for innate immunity: A focused review on RIG-I Signaling pathway. Frontiers in Immunology. 2022; 13 :951614 - 138.
El Kebir D et al. Bacterial DNA activates endothelial cells and promotes neutrophil adherence through TLR9 signaling. Journal of Immunology. 2009; 182 (7):4386-4394 - 139.
Fens MH et al. Erythrophagocytosis by angiogenic endothelial cells is enhanced by loss of erythrocyte deformability. Experimental Hematology. 2010; 38 (4):282-291 - 140.
Gao C et al. Endothelial cell phagocytosis of senescent neutrophils decreases procoagulant activity. Thrombosis and Haemostasis. 2013; 109 (6):1079-1090 - 141.
Ma R et al. Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis. Scientific Reports. 2017; 7 (1):4978 - 142.
Grutzendler J et al. Angiophagy prevents early embolus washout but recanalizes microvessels through embolus extravasation. Science Translational Medicine. 2014; 6 (226):226ra31 - 143.
van der Wijk A-E et al. Microembolus clearance through angiophagy is an auxiliary mechanism preserving tissue perfusion in the rat brain. Acta Neuropathologica Communications. 2020; 8 (1):195 - 144.
Marelli-Berg FM, Jarmin SJ. Antigen presentation by the endothelium: A green light for antigen-specific T cell trafficking? Immunology Letters. 2004; 93 (2-3):109-113 - 145.
Rothermel AL et al. Endothelial cells present antigens in vivo. BMC Immunology. 2004; 5 :5 - 146.
Leeuwenberg JF et al. Effects of tumor necrosis factor on the interferon-gamma-induced major histocompatibility complex class II antigen expression by human endothelial cells. European Journal of Immunology. 1988; 18 (9):1469-1472 - 147.
Tonk CH et al. Mesenchymal stem cells. In: Brand-Saberi B, editor. Essential Current Concepts in Stem Cell Biology. Cham: Springer International Publishing; 2020. pp. 21-39 - 148.
Jiang D et al. Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem Cells. Stem Cells. 2016; 34 (9):2393-2406 - 149.
Yang ZX et al. CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One. 2013; 8 (3):e59354 - 150.
Krasnodembskaya A et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010; 28 (12):2229-2238 - 151.
Gupta N et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax. 2012; 67 (6):533-539 - 152.
Hwa Cho H, Bae YC, Jung JS. Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells. 2006; 24 (12):2744-2752 - 153.
Kim HS et al. Implication of NOD1 and NOD2 for the differentiation of multipotent mesenchymal stem cells derived from human umbilical cord blood. PLoS One. 2010; 5 (10):e15369 - 154.
Lee JW et al. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. American Journal of Respiratory and Critical Care Medicine. 2013; 187 (7):751-760 - 155.
Stagg J et al. Interferon-gamma-stimulated marrow stromal cells: A new type of nonhematopoietic antigen-presenting cell. Blood. 2006; 107 (6):2570-2577 - 156.
Chan JL et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood. 2006; 107 (12):4817-4824 - 157.
Romieu-Mourez R et al. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-gamma, TGF-beta, and cell density. Journal of Immunology. 2007; 179 (3):1549-1558 - 158.
Hafen BB, Shook M, Burns B. Anatomy, Smooth Muscle. Treasure Island: StatPearls; 2022 - 159.
Hafen BB, Burns B. Physiology, Smooth Muscle. Treasure Island: StatPearls; 2022 - 160.
Sorokin V et al. Role of vascular smooth muscle cell plasticity and interactions in Vessel Wall inflammation. Frontiers in Immunology. 2020; 11 :599415 - 161.
Campbell GR et al. Degeneration and regeneration of smooth muscle transplants in the anterior eye chamber. An ultrastructural study. Zeitschrift für Zellforschung und Mikroskopische Anatomie. 1971; 117 (2):155-175 - 162.
Bennett MR, Sinha S, Owens GK. Vascular smooth muscle Cells in atherosclerosis. Circulation Research. 2016; 118 (4):692-702 - 163.
Clarke MC et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nature Medicine. 2006; 12 (9):1075-1080 - 164.
Libby P et al. Atherosclerosis. Nature Reviews Disease Primers. 2019; 5 (1):56 - 165.
Gui Y, Zheng H, Cao RY. Foam Cells in atherosclerosis: Novel insights into its origins, consequences, and molecular mechanisms. Frontier in Cardiovascular Medicine. 2022; 9 :845942 - 166.
Cookson FB. The origin of foam cells in atherosclerosis. British Journal of Experimental Pathology. 1971; 52 (1):62-69 - 167.
Allahverdian S et al. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 2014; 129 (15):1551-1559 - 168.
Gomez D, Owens GK. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovascular Research. 2012; 95 (2):156-164 - 169.
Shankman LS et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nature Medicine. 2015; 21 (6):628-637 - 170.
Herz J, Strickland DK. LRP: A multifunctional scavenger and signaling receptor. The Journal of Clinical Investigation. 2001; 108 (6):779-784 - 171.
Chen J et al. The dual role of low-density lipoprotein receptor-related protein 1 in atherosclerosis. Frontier in Cardiovascular Medicine. 2021; 8 :682389 - 172.
Grootaert MOJ et al. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovascular Research. 2018; 114 (4):622-634 - 173.
Seeberg JC et al. Non-professional phagocytosis: A general feature of normal tissue cells. Scientific Reports. 2019; 9 (1):11875